The overall objective of this proposal is to investigate the connective tissue biochemistry of emphysema utilizing a genetically controlled emphysema-prone strain of blotchy mouse. Specifically, we will relate any biochemical metabolic defects in lung collagen and elastin to the observed abnormalities in lung structure and function with emphasis on the amounts and molecular alterations in aldehydic intermolecular cross-links. Secondly, the biological role of the copper-dependent enzyme, lysyl oxidase in the pathogenesis of emphysema in blotchy mouse will be assessed. Finally, we will evaluate the lung injury and repair phenomena following inhaled oxidant pollutant exposure and elucidate the role of elastases (leukocyte and macrophage derived) in ozone-induced injury by the use of synthetic elastase inhibitors in-vivo. These studies may enhance our understanding of the role of inherited abnormalities of connective tissue synthesis in the pathogenesis of emphysema following environmentally-induced proteolytic lung injury. In addition, these studies may lead to new therapeutic approaches to the control and prevention of emphysema, a major cause of disability, morbidity and mortality in the United States.